Epigenetic regulation in gynecological cancers: a paradigm shift in immunotherapy strategies

Recent advances in immunotherapy have transformed the therapeutic landscape of gynecological cancers; however, durable responses remain limited by tumor heterogeneity and immune evasion mechanisms. Emerging evidence highlights epigenetic modifications comprising of DNA methylation, histone modifications, and RNA methylation as pivotal regulators of the tumor immune microenvironment and immunotherapy efficacy. This review comprehensively explores how these epigenetic alterations modulate immune cell infiltration, antigen presentation, immune checkpoint expression, and tumor immunogenicity across cervical, ovarian, and endometrial cancers. We also delineate the impact of specific epigenetic enzymes, such as DNMTs, HDACs, BET and RNA methyltransferases, in shaping immune responses and discuss the therapeutic potential of targeting these regulators to sensitize tumors to immune checkpoint inhibitors, cancer vaccines, cytokine based treatments and adoptive T-cell therapies. Furthermore, we examine the integration of epigenetic agents such as DNMT and HDAC inhibitors with immunotherapies in preclinical and clinical settings, emphasizing their synergistic capacity to overcome immunoresistance. By illuminating the interplay between epigenetic regulation and immune dynamics, this review underscores a paradigm shift toward precision immunoepigenetic strategies, offering a promising framework for enhancing therapeutic outcomes in gynecological malignancies.